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Article ; Online: Distinct peripheral T-cell and NK-cell profiles in HGBL-MYC/BCL2 vs patients with DLBCL NOS.

2024 Volume 8, Issue 5, Page(s) 1094–1104

Abstract: Abstract: Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) without a MYC ... ...

Abstract	Abstract: Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T cells and natural killer (NK) cells of patients with HGBL-MYC/BCL2 (n = 66), patients with DLBCL NOS (n = 53), and age-matched healthy donors (HDs; n = 16) by flow cytometry and performed proliferation, cytokine production, and cytotoxicity assays. Compared with HDs, both lymphoma subtypes displayed similar frequencies of CD8+ T cells but decreased CD4+ T cells. Regulatory T-cell (Treg) frequencies were reduced only in patients with DLBCL NOS. Activated (HLA-DR+/CD38+) T cells, PD-1+CD4+ T cells, and PD-1+Tregs were increased in both lymphoma subtypes, but PD-1+CD8+ T cells were increased only in HGBL-MYC/BCL2. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of senescent T cells than HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1+ T cells of patients with HGBL-MYC/BCL2 were exhausted with impaired cytokine production and degranulation. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of NK cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM-3+- and DNAM-1+-expressing NK cells. Although NK cells of patients with HGBL-MYC/BCL2 showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T cells of patients with HGBL-MYC/BCL2. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance of investigating potential immune evasion in the microenvironment of MYC-rearranged lymphomas.
MeSH term(s)	Humans ; Programmed Cell Death 1 Receptor ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Proto-Oncogene Proteins c-bcl-2/genetics ; T-Lymphocytes/pathology ; Killer Cells, Natural/pathology ; Cytokines ; Tumor Microenvironment
Chemical Substances	Programmed Cell Death 1 Receptor ; Proto-Oncogene Proteins c-bcl-2 ; Cytokines ; BCL2 protein, human
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011687
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Article ; Online: Graft-versus-leukemia in the bone marrow.

Klerk, Clara P W / Lam, King H

Blood

2014 Volume 123, Issue 4, Page(s) 470

MeSH term(s)	Biopsy ; Blood Component Transfusion ; Bone Marrow/metabolism ; Female ; Graft vs Host Disease/diagnosis ; Graft vs Leukemia Effect ; Humans ; Leukemia, Myeloid, Acute/blood ; Lymphocytes/cytology ; Middle Aged ; Remission Induction ; Stem Cell Transplantation ; T-Lymphocytes/cytology
Language	English
Publishing date	2014-02-25
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2013-09-528950
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Article ; Online: Etanercept for steroid-refractory acute graft-versus-host disease: A single center experience.

De Jong, Cornelis N / Saes, Lotte / Klerk, Clara P W / Van der Klift, Marjolein / Cornelissen, Jan J / Broers, Annoek E C

PloS one

2017 Volume 12, Issue 10, Page(s) e0187184

Abstract: ... days (range 47-267 days) for responders and 17 days (range 5-66 days) for non-responders (p<0.01 ...

Abstract	Background: Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic stem cell transplantation (alloSCT). High dose glucocorticosteroids, are currently recommended as first-line treatment for grade II-IV aGVHD resulting in overall complete responses (CR) in 40%-50% of patients. No standard second-line regimen has been established. Different options have been reported, including anti-TNFα antibodies. Methods: We retrospectively reviewed the outcome of 15 patients with steroid-refractory (SR) aGVHD treated with etanercept at our institution. Patients were transplanted for a hematological malignancy and received either a myeloablative or a non-myeloablative conditioning regimen. Prophylaxis of GVHD consisted of cyclosporin A and mycophenolic acid. Results: Acute GVHD was diagnosed at a median of 61 days post-transplantation. All patients had grade III aGVHD of the gut. Second-line treatment with etanercept was started at a median of 13 days after initiation of first-line therapy. Overall response rate was 53%, with CR in 3 patients and PR in 5 patients. Median overall survival after initiation of treatment with etanercept was 66 days (range 5-267) for the entire group. Median overall survival was 99 days (range 47-267 days) for responders and 17 days (range 5-66 days) for non-responders (p<0.01). Nevertheless, all patients died. Causes of death were progressive GVHD in 7 patients (47%), infection in 6 patients (40%), cardiac death in 1 patient (6.7%) and relapse in 1 patient (6,7%). Conclusion: Second-line treatment with etanercept does induce responses in SR-aGVHD of the gut but appears to be associated with poor long-term survival even in responding patients.
Keywords	covid19
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0187184
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Article ; Online: Disseminated intravascular coagulation at diagnosis is a strong predictor for thrombosis in acute myeloid leukemia.

Libourel, Eduard J / Klerk, Clara P W / van Norden, Yvette / de Maat, Moniek P M / Kruip, Marieke J / Sonneveld, Pieter / Löwenberg, Bob / Leebeek, Frank W G

Blood

2016 Volume 128, Issue 14, Page(s) 1854–1861

Abstract: Venous thromboembolism is a common complication in patients with cancer, but only limited data are available in acute myeloid leukemia (AML). In a prospective study in a cohort of 272 adult patients (aged 18-65) and an independent validation cohort of ... ...

Abstract	Venous thromboembolism is a common complication in patients with cancer, but only limited data are available in acute myeloid leukemia (AML). In a prospective study in a cohort of 272 adult patients (aged 18-65) and an independent validation cohort of 132 elderly adults (aged >60) with newly diagnosed AML, we assessed markers of disseminated intravascular coagulation (DIC) (fibrinogen, D-dimer, α-2-antiplasmin, antitrombin, prothrombin time, and platelet count) and the DIC score according the International Society of Thrombosis and Haemostasis and their associations with the occurrence of venous and arterial thrombosis during follow-up. The prevalence of thrombosis was 8.7% (4.7% venous, 4.0% arterial) in the younger adults over a median follow-up of 478 days and 10.4% (4.4% venous, 5.9% arterial) in elderly patients. Most thrombotic events (66%) occurred before the start of the second course of chemotherapy. The calculated DIC score significantly predicted venous and arterial thrombosis with a hazard ratio (HR) for a high DIC score (≥5) of 4.79 (1.71-13.45). These results were confirmed in the validation cohort of elderly patients with AML (HR 11.08 [3.23-38.06]). Among all DIC parameters, D-dimer levels are most predictive for thrombosis with an HR of 12.3 (3.39-42.64) in the first cohort and an HR of 7.82 (1.95-31.38) in validation cohort for a D-dimer >4 mg/L vs ≤4 mg/L. It is concluded that venous and arterial thrombosis may develop in ∼10% of AML patients treated with intensive chemotherapy, which to a large extent can be predicted by the presence of DIC at time of AML diagnosis.
MeSH term(s)	Adolescent ; Adult ; Aged ; Biomarkers/analysis ; Disseminated Intravascular Coagulation/complications ; Disseminated Intravascular Coagulation/diagnosis ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Leukemia, Myeloid, Acute/complications ; Middle Aged ; Predictive Value of Tests ; Prospective Studies ; Thrombosis/diagnosis ; Thrombosis/etiology ; Young Adult
Chemical Substances	Biomarkers ; Fibrin Fibrinogen Degradation Products ; fibrin fragment D
Language	English
Publishing date	2016-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2016-02-701094
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Article ; Online: Etanercept for steroid-refractory acute graft-versus-host disease

Cornelis N De Jong / Lotte Saes / Clara P W Klerk / Marjolein Van der Klift / Jan J Cornelissen / Annoek E C Broers

PLoS ONE, Vol 12, Iss 10, p e

A single center experience.

2017 Volume 0187184

Abstract: ... 66 days) for non-responders (p<0.01). Nevertheless, all patients died. Causes of death were ...

Abstract	Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic stem cell transplantation (alloSCT). High dose glucocorticosteroids, are currently recommended as first-line treatment for grade II-IV aGVHD resulting in overall complete responses (CR) in 40%-50% of patients. No standard second-line regimen has been established. Different options have been reported, including anti-TNFα antibodies.We retrospectively reviewed the outcome of 15 patients with steroid-refractory (SR) aGVHD treated with etanercept at our institution. Patients were transplanted for a hematological malignancy and received either a myeloablative or a non-myeloablative conditioning regimen. Prophylaxis of GVHD consisted of cyclosporin A and mycophenolic acid.Acute GVHD was diagnosed at a median of 61 days post-transplantation. All patients had grade III aGVHD of the gut. Second-line treatment with etanercept was started at a median of 13 days after initiation of first-line therapy. Overall response rate was 53%, with CR in 3 patients and PR in 5 patients. Median overall survival after initiation of treatment with etanercept was 66 days (range 5-267) for the entire group. Median overall survival was 99 days (range 47-267 days) for responders and 17 days (range 5-66 days) for non-responders (p<0.01). Nevertheless, all patients died. Causes of death were progressive GVHD in 7 patients (47%), infection in 6 patients (40%), cardiac death in 1 patient (6.7%) and relapse in 1 patient (6,7%).Second-line treatment with etanercept does induce responses in SR-aGVHD of the gut but appears to be associated with poor long-term survival even in responding patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Prophylactic plasma levels of the low molecular weight heparin nadroparin does not affect colon cancer tumor development in mouse liver.

Klerk, Clara P W / Niers, Tatjana M H / Brüggemann, Lois W / Smorenburg, Susanne M / Richel, Dick J / Spek, C Arnold / Van Noorden, Cornelis J F

Thrombosis research

2010 Volume 125, Issue 3, Page(s) 235–238

MeSH term(s)	Animals ; Heparin, Low-Molecular-Weight/therapeutic use ; Mice ; Mice, Inbred C57BL ; Nadroparin/therapeutic use ; Neoplasms/drug therapy
Chemical Substances	Heparin, Low-Molecular-Weight ; Nadroparin
Language	English
Publishing date	2010-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2009.03.005
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Article: Thrombosis prophylaxis in patient populations with a central venous catheter: a systematic review.

Klerk, Clara P W / Smorenburg, Susanne M / Büller, Harry R

Archives of internal medicine

2003 Volume 163, Issue 16, Page(s) 1913–1921

Abstract: Background: Central venous catheters (CVCs) are used in a wide variety of patients. Associated complications are thrombosis and infection. It is a matter of debate whether thromboprophylaxis is beneficial.: Methods: We performed a systematic review ... ...

Abstract	Background: Central venous catheters (CVCs) are used in a wide variety of patients. Associated complications are thrombosis and infection. It is a matter of debate whether thromboprophylaxis is beneficial. Methods: We performed a systematic review of 3 different patient populations to render the available information in the literature more accessible to clinical practice: patients receiving parenteral nutrition (PN), patients with cancer, and patients admitted to intensive care units. Results: Prophylaxis with heparin added to PN was found to give a nonsignificant reduction in the incidence of catheter-related thrombosis (pooled relative risk of randomized studies, 0.77; 95% confidence interval [CI], 0.11-5.48). In cancer patients, both low-dose warfarin and low-molecular-weight heparin significantly reduced the incidence of catheter-related thrombosis (relative risk of randomized studies, 0.25 [95% CI, 0.09-0.70] and 0.10 [95% CI, 0.01-0.71], respectively). So far, intensive care patients have hardly been studied with respect to thromboprophylaxis and the incidence of CVC thrombosis. Any effect of the type of catheter could not be established because of small numbers. There was no apparent increase in bleeding events with prophylactic anticoagulation in patients with CVCs. Conclusions: In the small number of patients studied, the addition of heparin to PN did not significantly decrease the risk of catheter-related thrombosis, whereas warfarin and dalteparin did decrease the thrombosis risk in cancer patients with CVCs. There is no apparent increase in bleeding events with prophylactic anticoagulants in patients with CVCs.
MeSH term(s)	Anticoagulants/therapeutic use ; Antineoplastic Agents/administration & dosage ; Catheterization, Central Venous/adverse effects ; Critical Illness/therapy ; Dalteparin/therapeutic use ; Heparin/therapeutic use ; Humans ; Intensive Care Units ; Neoplasms/drug therapy ; Parenteral Nutrition ; Randomized Controlled Trials as Topic ; Risk Factors ; Venous Thrombosis/etiology ; Venous Thrombosis/prevention & control ; Warfarin/therapeutic use
Chemical Substances	Anticoagulants ; Antineoplastic Agents ; Warfarin (5Q7ZVV76EI) ; Heparin (9005-49-6) ; Dalteparin (S79O08V79F)
Language	English
Publishing date	2003-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ZDB-ID	211575-x
ISSN	1538-3679 ; 0003-9926 ; 0888-2479 ; 0730-188X
ISSN (online)	1538-3679
ISSN	0003-9926 ; 0888-2479 ; 0730-188X
DOI	10.1001/archinte.163.16.1913
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Article: Antithrombotic therapy and cancer.

Di Nisio, Marcello / Squizzato, Alessandro / Klerk, Clara P W / Richel, Dick J / Büller, Harry R

Current opinion in hematology

2004 Volume 11, Issue 3, Page(s) 187–191

Abstract: Purpose of the review: To assess the current evidence from recent clinical trials investigating antithrombotic agents for the prophylaxis and treatment of venous thromboembolism in cancer patients and for the effects of these agents on cancer ... ...

Abstract	Purpose of the review: To assess the current evidence from recent clinical trials investigating antithrombotic agents for the prophylaxis and treatment of venous thromboembolism in cancer patients and for the effects of these agents on cancer progression. Recent findings: A growing body of evidence supports the preventive use of antithrombotic strategies in subgroups of cancer patients. Moreover, in the long-term management of deep venous thrombosis in cancer patients, low-molecular-weight heparin seems to represent a valid alternative to vitamin K antagonists. Finally, several studies have claimed a direct anticancer activity and a positive impact on prognosis of some antithrombotic agents, eg, aspirin and low-molecular-weight heparin. Summary: Although recent evidence suggests low-molecular-weight heparin as a possible option in the management and prevention of venous thromboembolism in cancer patients, more evidence from large randomized, prospective, controlled trials is needed to determine the exact the magnitude of the risk-benefit ratio associated with its use. The promising results on the effects of antithrombotic agents in the prognosis of cancer patients deserve further evaluation to estimate the potential and the feasibility of this approach.
MeSH term(s)	Anticoagulants/therapeutic use ; Clinical Trials as Topic ; Humans ; Neoplasms/complications ; Thromboembolism/drug therapy ; Thromboembolism/etiology ; Thromboembolism/prevention & control ; Venous Thrombosis/drug therapy ; Venous Thrombosis/etiology ; Venous Thrombosis/prevention & control
Chemical Substances	Anticoagulants
Language	English
Publishing date	2004-07-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/01.moh.0000130317.18163.83
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Zs.A 3703: Show issues

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Article ; Online: Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung.

Niers, Tatjana M H / Brüggemann, Lois W / Klerk, Clara P W / Muller, Femke J M / Buckle, Tessa / Reitsma, Pieter H / Richel, Dick J / Spek, C Arnold / Van Tellingen, Olaf / Van Noorden, Cornelis J F

Clinical & experimental metastasis

2008 Volume 26, Issue 3, Page(s) 171–178

Abstract: ... low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L- and P-selectin ... protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L- and P-selectins. Hirudin inhibited tumor development ...

Abstract	Cancer progression is facilitated by blood coagulation. Anticoagulants, such as Hirudin and low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L- and P-selectin-mediated cell-cell adhesion. It is unknown whether the effects are dependent on cancer cell type. The effects of anticoagulants on tumor development of K1735 and B16 melanoma cells and CT26 colon cancer cells were investigated in mouse lung. Tumor load was determined noninvasively each week up to day 21 in all experiments using bioluminescence imaging. Effects of anticoagulants on tumor development of the three cell lines were correlated with the fibrin/fibrinogen content in the tumors, expression of tissue factor (TF), protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L- and P-selectins. Hirudin inhibited tumor development of B16 cells in lungs completely but did not affect tumor growth of K1735 and CT26 cells. Low molecular weight heparin did not have an effect on K1735 melanoma tumor growth either. TF and PAR-4 expression was similar in the three cell lines. PAR-1 and CD24 were hardly expressed by K1735, whereas CT26 cells expressed low levels and B16 high levels of PAR-1 and CD24. Fibrin content of the tumors was not affected by LMWH. It is concluded that effects of anticoagulants are dependent on cancer cell type and are correlated with their CD24 and PAR-1 expression.
MeSH term(s)	Animals ; Anticoagulants/pharmacology ; Anticoagulants/therapeutic use ; Blood Coagulation/drug effects ; CD24 Antigen/metabolism ; Cell Line, Tumor ; Fibrin/metabolism ; Fibrinogen/metabolism ; Heparin, Low-Molecular-Weight/pharmacology ; Heparin, Low-Molecular-Weight/therapeutic use ; Hirudins/pharmacology ; Lung Neoplasms/blood supply ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Lung Neoplasms/secondary ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; P-Selectin/metabolism ; Receptor, PAR-1/metabolism ; Thromboplastin/biosynthesis ; Transplantation, Heterologous
Chemical Substances	Anticoagulants ; CD24 Antigen ; Heparin, Low-Molecular-Weight ; Hirudins ; P-Selectin ; Receptor, PAR-1 ; Fibrin (9001-31-4) ; Fibrinogen (9001-32-5) ; Thromboplastin (9035-58-9)
Language	English
Publishing date	2008-12-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604952-7
ISSN	1573-7276 ; 0262-0898
ISSN (online)	1573-7276
ISSN	0262-0898
DOI	10.1007/s10585-008-9227-6
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Article: Validity of bioluminescence measurements for noninvasive in vivo imaging of tumor load in small animals.

Klerk, Clara P W / Overmeer, Renée M / Niers, Tatjana M H / Versteeg, Henri H / Richel, Dick J / Buckle, Tessa / Van Noorden, Cornelis J F / van Tellingen, Olaf

BioTechniques

2007 Volume 43, Issue 1 Suppl, Page(s) 7–13, 30

Abstract: A relatively new strategy to longitudinally monitor tumor load in intact animals and the effects of therapy is noninvasive bioluminescence imaging (BLI). The validity of BLIf or quantitative assessment of tumor load in small animals is critically ... ...

Abstract	A relatively new strategy to longitudinally monitor tumor load in intact animals and the effects of therapy is noninvasive bioluminescence imaging (BLI). The validity of BLIf or quantitative assessment of tumor load in small animals is critically evaluated in the present review. Cancer cells are grafted in mice or rats after transfection with a luciferase gene--usually that of a firefly. To determine tumor load, animals receive the substrate agent luciferin intraperitoneally, which luciferase converts into oxyluciferin in an ATP-dependent manner Light emitted by oxyluciferin in viable cancer cells is captured noninvasively with a highly sensitive charge-coupled device (CCD) camera. Validation studies indicate that BLI is useful to determine tumor load in the course of time, with each animal serving as its own reference. BLI is rapid, easy to perform, and sensitive. It can detect tumor load shortly after inoculation, even when relatively few cancer cells (2500-10,000) are used. BLI is less suited for the determination of absolute tumor mass in an animal because of quenching of bioluminescence by tissue components and the exact location of tumors because its spatial resolution is limited. Nevertheless, BLI is a powerful tool for high-throughput longitudinal monitoring of tumor load in small animals and allows the implementation of more advanced orthotopic tumor models in therapy intervention studies with almost the same simplicity as when measuring traditional ectopic subcutaneous models in combination with calipers.
MeSH term(s)	Animals ; Cell Count/instrumentation ; Cell Count/methods ; Cell Count/trends ; Cell Count/veterinary ; Disease Models, Animal ; Humans ; Luminescent Measurements/instrumentation ; Luminescent Measurements/methods ; Luminescent Measurements/trends ; Luminescent Measurements/veterinary ; Neoplasm Staging/instrumentation ; Neoplasm Staging/methods ; Neoplasm Staging/trends ; Neoplasm Staging/veterinary ; Neoplasms/pathology ; Neoplasms/veterinary
Language	English
Publishing date	2007-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review ; Validation Studies
ZDB-ID	48453-2
ISSN	1940-9818 ; 0736-6205
ISSN (online)	1940-9818
ISSN	0736-6205
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